Simple theory predicts that adding time-of-flight (TOF) information reduces the noise in PET images. This noise reduction can improve image quality, decrease imaging time, decrease injected dose, or achieve a combination of these benefits. The potential impact on translational medicine is large, especially for oncology studies in large patients, where improvement is sorely needed. Thus, time-of-flight PET has received considerable interest, with commercialization of TOF PET cameras in the last five years. All of these commercial TOF PET cameras achieve ~555 ps fwhm timing resolution, but as the noise variance in the image is proportional to the timing resolution (i.e., reducing the timing resolutio by a factor of two implies a factor of two reduction in either the imaging time or dose), there is desire to obtain the best timing resolution possible. In addition, the way in which this noise reduction translates into clinical benefit is not well understood. The purpose of this proposal is o build a prototype PET camera whose timing resolution is ~150 ps fwhm (almost four times better than what commercial TOF PET cameras achieve), devise methods to quantify how the noise reduction afforded by time-of-flight translates into clinical benefit, and then measure (usin the prototype camera) how image improvement depends on the timing resolution. By devising methods for obtaining better timing resolution and by quantifying the TOF benefits as a function of timing resolution, we will guide future commercial and academic TOF PET camera designers by allowing them to make informed choices, as our technical developments have been and will continue to be open source. We plan three main developments. In the previous funding cycle, we constructed a single-ring demonstration TOF PET camera with LSO scintillator crystals that achieves 326 ps coincidence timing resolution. While simple estimates predict that it will reduce the noise variance by a factor of roughly two in whole-body imaging compared to commercial TOF PET cameras, the first task is to perform a thorough analysis to better characterize its clinical utility. Specifically, we will quantify the improvement in noise as a function of timing resolution using a combination of simulation, phantom, and human subject studies, including the clinically relevant tasks of tumor detection and staging. Our second task is to rebuild the camera with a newly developed scintillator (LaBr3:Ce) that has exceptional PET performance (high sensitivity, 3% energy resolution, and 150 ps timing resolution), which will provide another factor of two improvement in timing resolution over our LSO camera. This timing resolution is nearly four times better than commercial TOF PET cameras, and we predict it will give an enormous noise variance reduction (16-fold, when imaging a 35 cm diameter patient) compared to conventional (non-TOF) PET cameras! The final task is to analyze the performance of this camera by using the same methods as in the first task.